Handbook of pharmaceutic vol 6 sterile products

H A N D B O O K

O F

Pharmaceutical
Manufacturing
Formulations
Sterile Products
VOLUME 6

© 2004 by CRC Press LLC


Handbook of
Pharmaceutical Manufacturing Formulations
Volume Series
Sarfaraz K. Niazi
Volume 1
Handbook of Pharmaceutical Manufacturing Formulations:
Compressed Solid Products
Volume 2
Handbook of Pharmaceutical Manufacturing Formulations:
Uncompressed Solid Products
Volume 3
Handbook of Pharmaceutical Manufacturing Formulations:
Liquid Products
Volume 4
Handbook of Pharmaceutical Manufacturing Formulations:
Semisolid Products
Volume 5
Handbook of Pharmaceutical Manufacturing Formulations:

V
O L U MProducts
E 1
Over-the-Counter
Volume 6
Handbook of Pharmaceutical Manufacturing Formulations:
Sterile Products

© 2004 by CRC Press LLC


H A N D B O O K

O F

Pharmaceutical
Manufacturing
Formulations
Sterile Products
VOLUME 6

Sarfaraz K. Niazi

CRC PR E S S
Boca Raton London New York Washington, D.C.

© 2004 by CRC Press LLC


Library of Congress Cataloging-in-Publication Data

Niazi, Sarfaraz, 1949–
Handbook of pharmaceutical manufacturing formulations / Sarfaraz K. Niazi.
p. cm.
Includes bibliographical references and index.
Contents: — v.6. Sterile products.
ISBN 0-8493-1751-7 (alk. paper)
1. Drugs—Dosage forms—Handbooks, manuals, etc. I. Title
RS200.N53 2004
615'19—dc21
2003051451

This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted with permission, and
sources are indicated. A wide variety of references are listed. Reasonable efforts have been made to publish reliable data and information,
but the author and the publisher cannot assume responsibility for the validity of all materials or for the consequences of their use.
Neither this book nor any part may be reproduced or transmitted in any form or by any means, electronic or mechanical, including
photocopying, microfilming, and recording, or by any information storage or retrieval system, without prior permission in writing from
the publisher.
The consent of CRC Press LLC does not extend to copying for general distribution, for promotion, for creating new works, or for resale.
Specific permission must be obtained in writing from CRC Press LLC for such copying.
Direct all inquiries to CRC Press LLC, 2000 N.W. Corporate Blvd., Boca Raton, Florida 33431.
Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and
explanation, without intent to infringe.

Visit the CRC Press Web site at www.crcpress.com
© 2004 by CRC Press LLC
No claim to original U.S. Government works
International Standard Book Number 0-8493-1751-7
Library of Congress Card Number 2003051451
Printed in the United States of America 1 2 3 4 5 6 7 8 9 0
Printed on acid-free paper

© 2004 by CRC Press LLC


Dedication
To Professor Shamsuz Zoha, my first pharmacy teacher, who inspired many
with his passion for the profession and for science

© 2004 by CRC Press LLC


Preface to the Series
No industry in the world is more highly regulated than
the pharmaceutical industry because of potential threat to
a patient’s life from the use of pharmaceutical products.
The cost of taking a new chemical entity (amortized over
the cost of all molecules racing) to final regulatory
approval is a staggering $800 million, making the pharmaceutical industry one of the most research-intensive
industries in the world. In the year 2004, it is anticipated
that the industry will spend about $20 billion on research
and development. The generic market of drugs as the new
entities come off patent is one of the fastest growing
segments of the pharmaceutical industry, with every major
multinational company having a significant presence in
this field.
Whereas many stages of new drug development are
inherently constrained with time, the formulation of drugs
into desirable dosage forms remains an area where expediency can be practiced with appropriate knowledge by
those who have mastered the skills of pharmaceutical formulations. The Handbook of Pharmaceutical Manufacturing Formulations is the first major attempt to consolidate
the available knowledge about formulations in a comprehensive, and by nature a rather voluminous, presentation.

The book is divided into six volumes, based strictly
on the type of formulation science involved in the development of these dosage forms: sterile products, compressed solids, uncompressed solids, liquid products,
semisolid products, and OTC products. The separation of
OTC products even though they may easily fall into one
of the other five categories is made to comply with the
industry norms of separate research divisions for OTC
products. Sterile products require skills related to sterilization of product, and of less importance is the bioavailability issue, which is an inherent problem of compressed

© 2004 by CRC Press LLC

dosage forms. These types of considerations have led to
the classification of products into these six categories.
Each volume includes a description of regulatory filing techniques for the formulations described. Also
included are the current regulatory guidelines on cGMP
compliance specific to the dosage form. Advice is offered
on how to scale up the production batches.
It is expected that formulation scientists will use this
information to benchmark their internal development protocols and cut the race to file short by adopting formulae
that have survived the test of time. Many of us who have
worked in the pharmaceutical industry suffer from a close
paradigm when it comes to selecting formulations — “not
invented here” perhaps reigns in the mind of many seasoned formulations scientists subconsciously when they
prefer to choose only a certain platform for development.
It is expected that with the quick review of possibilities
available to formulate made available in this book, scientists will benefit from the experience of others.
For the teachers of formulation sciences, this series
offers a wealth of information. Whether it is a selection
of a preservative system or the choice of a disintegrant,
the series offers a wide choice to study and rationalize.
Many have assisted me in the development of this

work that has taken years to compile, and I thank scores
of my graduate students and colleagues for their help. A
work of this size cannot be produced without errors,
although I hope that these errors do not distract the reader
from the utility of the book. I would sincerely appreciate
if readers point out these mistakes for corrections in future
editions.
Sarfaraz K. Niazi, Ph.D.
Deerfield, Illinois


Preface to the Volume
The Handbook of Pharmaceutical Manufacturing Formulations: Sterile Products (HPMF/SP) is written for the
pharmaceutical scientist and others involved in the regulatory filing and manufacturing of new sterile products.
No other area of regulatory compliance receives more
attention and scrutiny by regulatory authorities than the
regulation of sterile products, for obvious reasons. With
the increasing number of potent products, particularly the
new line of small protein products, joining the long list
of proven sterile products — mainly parenteral and ophthalmic products — the technology of manufacturing sterile products has evolved into a very sophisticated industry.
The entry barrier to this technology is much higher compared with those for other dosage forms. Consequently,
the cost of production remains high as well. In recent
years, regulatory agencies around the world have taken
very serious notice of the deficiencies in the manufacturing specifications of the active raw material intended for
parenteral administration. New guidelines for the API and
aseptic processing of sterile products are the main issues
of concern today for manufacturers. This volume of
HPMF/SP does not delve into details related to starting
material issues. Of interest in this issue are formulations
of sterile dosage forms, regulatory filing requirements of

sterile preparations, and cGMP compliance, all of which
are tied together in the final preparation of the Chemistry,
Manufacturing, and Control (CMC) sections of regulatory
applications.
Chapter 1 describes the specifications of a manufacturing facility to manufacture compliant sterile products.
Chapter 2 outlines the New Drug Application (NDA) or
ANDA (Abbreviated New Drug Application) filing
requirements of sterile products. Chapter 3 describes in
detail the layout of formulations provided in the book.
This chapter must be thoroughly examined to make the
best use of this book. Because the intent of the information
provided in this book is to help the formulator develop a
product for regulatory filing, boilerplate details are left
out. Chapter 3 provides these details and also makes strong
recommendations on how the formulator can benefit from
the information available from suppliers of components
and chemicals used in the formulation.
These three chapters are followed by the body of the
book, which provides an alphabetical presentation of formulations of pharmaceutical products based on their
generic names. There are three types of formulation
entries. In the first type, both the bill of materials and

© 2004 by CRC Press LLC

manufacturing directions are provided. This type is further
composed of two types, wherein greater detail is provided
for some products. This differentiation is intentional
because the common details are often omitted in subsequent presentations. The second type of formulations is
provided with bill of materials only. This may include
products for which the manufacturing directions are obvious to a prospective manufacturer, particularly in light of

the details already provided for similar products elsewhere
in the book, and also those products for which such information is not readily available. The third category of formulations includes experimental formulations, which may
not yet have been commercialized or received regulatory
approvals. These formulations are included to show to the
formulation scientist unique opportunities that exist for
the chemical entity in question.
Formulations of biotechnology-derived drugs are
provided with some additional details and remain
restricted to declaration of composition, yet they provide
a good overview of the complexities involved in such
formulations.
In consolidating the details of formulations, efforts
have been made to present them in as unified a form as
possible; nevertheless, some nonuniformities exist
because of the large variety of presentations possible for
the wide diversity of formulations presented in the book.
A limited number of products intended for veterinary use
are also included. These products are subject to cGMP
compliance similar to that for human products.
The formulations provided here meet the 4S
requirements:
•

•

•

Safety. This is an important issue for parenteral
products; the choice of excipients is limited by
this consideration. In most of the formulations,

the ingredients are fully approved by the regulatory authorities; in some formulations, the
active drug moiety may have been banned in
some countries, for example, dipyrone.
Sterility. The compositions presented are fully
sterilizable either by terminal treatment or by
aseptic processing; where preservatives are
added, these are in sufficient quantity to fulfill
the dedicated function.
Stability. Besides the rigor of treatment in rendering a product sterile, incompatibility issues
may render a sterile product prone to instability.


•

The formulations included here have been fully
validated to provide sufficient shelf-life,
depending on the product.
Scalability. Whereas the batch formulation is
presented for a 1-l batch, these formulations are
linearly scalable. Manufacturing losses have
been included and these formulations can be
readily scaled up to any size; of course, the
requirements of size change in the validation
protocol should be considered.

One of the best utilities of the database included in this
book is to benchmark the products intended for development. A large number of formulation possibilities exist
for any drug; though with the 4S limitations, the choice
of ingredients (excipients) narrows rather rapidly. Multivitamin formulations are one such example wherein
extreme instability and cost considerations have resulted

in a variety of formulations. A study of many possibilities
tells us about the problems we can anticipate while formulating these products. In some instances, only composition details are provided, along with raw material manufacturing details, because they are often an integral part
of the formulation, such as in the case of biotechnologyderived products. Whereas this information may be at best
cursory, it is useful to provide a study of these product
formulations.
The information contained in this book has been
obtained mainly from sources open to the public. It has
taken years to accumulate this database and no warranties
are provided that these formulation compositions will not
infringe on any proprietary product or intellectual property. The formulators must consider this before using the
information. Also, as with all scientific experimental data,
it should be understood that replication is subject to many
factors, including type of equipment used, grade of material employed, and other processing techniques implemented. The road to converting these formulations to

© 2004 by CRC Press LLC

validated parts of a CMC package for submission to regulatory authorities is a long one; nevertheless, working
with these formulations will reduce the risk of prolonged
experimentation, and for generic formulation development, it will expedite entrance to the market. Some scientists may find this information useful in improving their
products for any of the 4S considerations. More information is available on the website of Pharmaceutical Scientist, Inc. (), wherein scientists
can find updated information on regulatory compliance
and additional tools for writing the CMC portions of the
ANDA and NDA filings. The readers are encouraged to
consult this website.
Although I have tried to sift through the large databases in both the formative and proofreading stages of the
handbook, it is possible that errors remain. I would appreciate it if readers point these out to me by e-mailing me
at
I am grateful to CRC Press for taking this lead in
publishing what is possibly the largest such work in the
field of pharmaceutical sciences. It has been a distinct

privilege to know Mr. Stephen Zollo, senior editor at CRC
Press. Stephen has done more than what any editor can
do to encourage an author into conceiving, planning, drafting, and finally, despite many reasons why it could not be
done, completing the work on a timely basis. I am greatly
indebted to him. The editorial assistance provided by CRC
Press staff was indeed exemplary, particularly the help
given by Erika Dery, Gail Renard, Sara Kreisman, and
others at CRC Press. Although the editors and proofreaders have pored over this book diligently, any mistakes
remaining are altogether mine.
Sarfaraz K. Niazi, Ph.D.
Pharmaceutical Scientist, Inc.
20 Riverside Drive
Deerfield, Illinois 60015


About the Author
Dr. Sarfaraz K. Niazi has been teaching and conducting research in the pharmaceutical industry for over 30 years. He has authored hundreds of scientific papers,
textbooks, and presentations on the topics of pharmaceutical formulation, biopharmaceutics, and pharmacokinetics of drugs. He is also an inventor with scores of
patents and is licensed to practice law before the U.S. Patent and Trademark Office.
Having formulated hundreds of products from consumer products to complex biotechnology-derived products, he has accumulated a wealth of knowledge in the
science of formulations and regulatory filings of Investigational New Drugs (INDs)
and New Drug Applications (NDAs). Dr. Niazi advises the pharmaceutical industry
internationally on issues related to formulations, pharmacokinetics and bioequivalence
evaluation, and intellectual property issues ().

© 2004 by CRC Press LLC


Table of Contents
Part I

Sterile Manufacturing Practice
Chapter 1
Inspection of Sterile Product Manufacturing Facilities
I.
Introduction
II. cGMP Compliance Basics
A. Personnel
B. Buildings
C. Air
D. Environmental Controls
E.
Equipment
F.
Water for Injection
G. Containers and Closures
H. Sterilization
1. Methods
2. Indicators
3. Filled Containers
I.
Personnel Practices
J.
Laboratory Controls
1. Retesting for Sterility
2. Retesting for Pyrogens
3. Particulate Matter Testing
4. Production Records
III. Aseptic Processing
A. Introduction
B. Buildings and Facilities

1. Critical Area (Class 100)
2. Supporting Clean Areas
3. Clean Area Separation
4. Air Filtration
5. Design
C. Personnel Training, Qualification, and Monitoring
1. Manufacturing Personnel
2. Laboratory Personnel
3. Monitoring Program
D. Components and Containers/Closures
1. Components
2. Containers/Closures
E.
Endotoxin Control
F.
Time Limitations
G. Process Validation and Equipment Qualification
1. Process Simulations
2. Filtration Efficacy
3. Sterilization of Equipment and Containers/Closures

© 2004 by CRC Press LLC


H.

Laboratory Controls
1. Environmental Monitoring
2. Microbiological Media and Identification
I.

Sterility Testing
1. Choice of Methods
2. Media
3. Personnel
4. Sampling and Incubation
5. Investigation of Sterility Positives
J.
Batch Record Review: Process Control Documentation
IV. Processing Prior to Filling and Sealing Operations
A. Aseptic Processing from Early Manufacturing Steps
B. Aseptic Processing of Cell-Based Therapy Products (or of Products Intended for Use
as Cell-Based Therapies)
V.
Aseptic Processing Isolators
A. Maintenance
1. General
2. Glove Integrity
B. Design
1. Airflow
2. Materials of Construction
3. Pressure Differential
4. Clean-Area Classifications
C. Transfer of Materials and Supplies
1. Introduction
2. Discharge
D. Decontamination
1. Surface Exposure
2. Efficacy
3. Frequency
E.

Filling Line Sterilization
F.
Environmental Monitoring
G. Personnel
VI. Blow-Fill-Seal Technology
A. Equipment Design and Air Quality
B. Validation and Qualification
C. Batch Monitoring and Control
VII. Lyophilization of Parenterals
A. Introduction
B. Product Type and Formulation
C. Filling
D. Lyophilization Cycle and Controls
E.
Cycle Validation
F.
Lyophilizer Sterilization and Design
G. Finished Product Testing
1. Dose Uniformity
2. Stability Testing
3. Sterility Testing
H. Finished Product Inspection — Meltback
VIII. High-Purity Water Systems
A. System Design
B. System Validation
C. Microbial Limits
1. WFI Systems
2. Purified Water Systems

© 2004 by CRC Press LLC

D.
E.
F.
G.
H.
I.
J.
K.
L.
M.
References

WFI Systems
Still
Heat Exchangers
Holding Tank
Pumps
Piping
Reverse Osmosis
Purified Water Systems
Process Water
Evaluation Strategy

Chapter 2
New Drug Application for Sterilized Products
I.
Introduction
II. Terminal Heat Sterilization

A. Description of the Process and Product
B. Thermal Qualification of the Cycle
C. Microbiological Efficacy of the Cycle
D. Microbiological Monitoring of the Environment
E.
Container/Closure and Package Integrity
F.
Bacterial Endotoxins Test and Method
G. Sterility Testing Methods and Release Criteria
H. Evidence of Formal Written Procedures
III. Other Terminal Sterilization Processes
A. Ethylene Oxide
B. Radiation
IV. Aseptic Fill Manufacturing Processes
A. Buildings and Facilities
B. Overall Manufacturing Operation
C. Containers and Closures
D. Procedures and Specifications for Media Fills
E.
Actions Concerning Product when Media Fills Fail
F.
Microbiological Monitoring of the Environment
G. Container/Closure and Package Integrity
H. Sterility Testing Methods and Release Criteria
I.
Bacterial Endotoxins Test and Method
J.
Evidence of Formal Written Procedures
V.
Maintenance of Microbiological Control and Quality: Stability Considerations

A. Container/Closure Integrity
B. Preservative Effectiveness
C. Pyrogen or Endotoxin Testing
Chapter 3
Manufacturing Formulations Template
Autoclaves
Aseptic Contract Manufacturers
Clean Room Design and Construction
Clean-in-Place/Steam-in-Place (CIPISIP)
Closure Washing and Sterilization
Consultants
Disinfectants and Preservatives
Distillation Equipment
Engineering and Construction

© 2004 by CRC Press LLC


Filling Machines
Filter Aids
Flowmeters (Sanitary)
Freeze-Dryers (Sterilizable)
Microfiltration Equipment and Filters
Pumps (Sanitary)
Sterile Tanks and Related Stainless Equipment
Sterility Test Equipment .
Sterilizing and Drying Tunnels (Hot Air)
Stoppering Machines
Vial and Bottle Washers

Part II
Sterile Pharmaceutical Formulations
Abciximab Injection
Acetazolamide Injection
Acetylcholine Chloride Intraocular Solution
Acyclovir Sodium Injection
Adenosine Injection
Adrenal Cortex Injection
Adrenaline Tartarate Injection
Alatrofloxacin Mesylate Injection
Albumin (Human)
Albuterol Sulfate Inhalation Solution
Aldesleukin for Injection
Alemtuzumab Injection
Alpha Tocopherol (Vitamin E) Injection
Alprostadil for Injection
Alteplase Recombinant Injection
Amikacin Sulfate Injection
Amino Acid Parenteral Nutrition Solution
Aminohippurate Sodium for Injection
Aminophylline Injection
Amiodarone Injection
Amoxicillin–Clavulanic Acid Injection
Amoxicillin Powder for Injection
Amphotericin B Cholesteryl Sulfate Complex for Injection
Amphotericin B Injection
Amphotericin B Lipid Complex Injection
Amphotericin B Liposome for Injection
Antazoline Sulfate and Xylometazoline Hydrochloride Ophthalmic Drops
Antipyrine, Phenylephrine, and Pyrilamine Maleate Ophthalmic Drops

Antipyrine, Phenylephrine, and Sodium Thiosulfate Ophthalmic Solution
Antithymocyte Globulin (Rabbit) for Injection
Aprotinin Injection
Argatroban (Thrombin Inhibitor) Injection
Arsenic Trioxide Injection
Ascorbic Acid and B-Complex Vitamins
Ascorbic Acid, B-Complex Vitamin, with Beta Carotene Injection
Ascorbic Acid Injection
Ascorbic Acid, USP, Injection
Ascorbic Acid, USP, 250 mg/mL Injection
Asparaginase for Injection

© 2004 by CRC Press LLC


Atropine, Chlorpheniramine Maleate, and Phenylpropanolamine Injection
Atropine Sulfate Injection
Aztreonam for Injection
Basiliximab for Injection
B-Complex Injection
B-Complex, Vitamin D, Vitamin E Lyophilized Injection
B-Complex Vitamin Veterinary
B-Complex with Minerals Injection (Veterinary)
B-Complex Vitamins with Hormones.
B-Complex Vitamins with Liver Extract Injection
Benzodiazepine Injection
Benztropine Mesylate Injection
Beta-Carotene Injection
Betamethasone Suspension Injection
Bethanechol Chloride Injection

Biotin Injection
Biperiden Lactate Injection
Bisantrene Emulsion Injection
Borax Sodium Lubricating Ophthalmic Drops
Botulinum Toxin
Bretylium Tosylate in Dextrose Injection
Buflomedil Injection
Bupivacaine Hydrochloride Injection
Buprenorphine Hydrochloride Injectable
Caffeine Citrate Injection
Calcitonin Injection
Calcitriol Injection
Calcium Glycerophosphate Injection
Calcium Injection
Camphor Injection
Camptothecin Injection
Carboplatin for Infusion
Carboplatin Injection
Carprofen Injection
Cefamandole Nafate for Injection
Cefazolin Injection
Cefepime Hydrochloride for Injection
Cefotaxime Injection
Cefotetan Injection
Cefoxitin Injection Premixed Intravenous Solution
Ceftazidime for Injection — L-Arginine Formulation
Ceftazidime Injection
Ceftriaxone Injection
Cefuroxime for Injection
Cetrorelix Acetate for Injection

Chloramphenicol and Phenylmercuric Nitrate Ophthalmic Drops
Chloramphenicol for Injection
Chloramphenicol Injection
Chloramphenicol Sodium Succinate for Injection
Chlordiazepoxide Hydrochloride Injection
Chloroprocaine Hydrochloride Injection
Chloroquine Phosphate Injection
Chlorothiazide Sodium for Injection
Chlorpheniramine Maleate Injection
Chlorpromazine Hydrochloride Injection

© 2004 by CRC Press LLC


Choriogonadotropin Alfa (Recombinant) for Injection
Chorionic Gonadotropin for Injection
Chromium Chloride Additive Injection
Cidofovir Injection
Cimetidine Injection
Ciprofloxacin Hydrochloride Ophthalmic Solution
Ciprofloxacin Injection
Cisplatin Diaminedichloride Injection
Cisplatin with 2,2¢-Dithio-bis-Ethane Sulfonate Injection
Cladribine Injection Infusion
Clarithromycin Injection
Clindamycin Injection in 5% Dextrose
Clindamycin Phosphate Injection
Clonidine Hydrochloride Injection
Coagulation Factor VIIa (Recombinant) for Injection
Coagulation Factor IX (Recombinant) for Injection

Colistin Sulfate, Neomycin Sulfate, Thonzonium Bromide, and Hydrocortisone Acetate Otic Suspension
Conjugated Estrogens for Injection
Copper Sulfate Additive Injection
Corticorelin Ovine Triflutate for Injection
Cortisone Acetate Injectable Suspension
Cosyntropin for Injection
Cromolyn Sodium Ophthalmic Solution
Crude Liver Extract Injection
Cyanocobalamin and Thiamine Injection
Cyanocobalamin, Choline, and Niacinamide Injection
Cyanocobalamin Injection
Cyanocobalamin Injection for Veterinary Use
Cyanocobalamin Repository Injection 1000 mg/mL
Cyanocobalamin, Pyridoxine, and Thiamine Injection
Cyclosporine Ampoules for Infusion
Cytarabine Liposome Injection for Intrathecal Use, 50 mg/5 mL Vial
Cytomegalovirus Immune Globulin Intravenous (Human)
Dacarbazine Injection
Daclizumab for Injection
Dactinomycin for Injection
Dalteparin Sodium Injection
Danaparoid Sodium Injection
Dantrolene Sodium for Injection
Dapiprazole Hydrochloride Ophthalmic Solution, 0.5%
Daunorubicin
Desmopressin Acetate Injection-Intranasal
Dexamethasone Acetate Suspension Injection
Dexpanthenol, Niacinamide, Pyridoxine, Riboflavin, and Thiamine Injection
Dexrazoxane for Injection
Dextrose 25% Injection (Flexible Container)

Dextrose Injection 5% and 10% LVP
Dextrose with Sodium Chloride Injection LVP
Diazepam Emulsion Injection
Diazepam Injection
Diazepam Rectal Solution
Dibenzazepine Carboxamide Injection
Diclofenac Injection
Dicyclomine Hydrochloride Injection
Digoxin Injection

© 2004 by CRC Press LLC


Dihydroergotamine Mesylate Drops
Dihydroergotamine Mesylate Injection
Dihydroergotamine Mesylate Nasal Spray
Diisopropylphenol Injection
Diltiazem Hydrochloride Injection
Dimenhydrinate Injection
Dimethyl Sulfoxide Injection
Dinoprostone Cervical Gel
Diphenhydramine Hydrochloride Injection
Diphenylmethyl Piperazine Injection
Dipyrone Injection
Dipyrone, Papaverine HCl, and Atropine Sulfate Injection
Disodium Edetate Injection.
Disulfonic Acids Injection
Dobutamine Injection
Dopamine Hydrochloride Injection
Doxapram Hydrochloride Injection, USP

Doxercalciferol Injection
Doxorubicin for Injection
Doxycycline Hyclate Injection
Doxycycline Hydrochloride Injection
Ebselen Liposomal Injection
Edetate Sodium, Polyvinyl Alcohol, Sodium Sulfacetamide, Sodium Thiosulfate Ophthalmic Drops
Edrophonium Injectable
Electrolyte Maintenance Fluid
Electrolytes, TPN Injection
Emetine Hydrochloride Injection
Enalaprilat Injection
Ephedrine and Pyrilamine Maleate Injection Veterinary
Ephedrine Sulfate Injection
Epinephrine Auto Injector Injection
Epinephrine Injection
Epoetin Alfa for Injection
Epoprostenol Sodium for Injection
Ergocalciferol Injection (Vitamin D)
Ergonovine Maleate Injection
Ergonovine Maleate Injection Veterinary
Erythromycin Injection
Esmolol Hydrochloride Injection
Estradiol Cypionate Injection
Estradiol Suspension Injection
Estradiol Valerate Injection
Estrogenic Substances in Oil Injection
Estrone, Estradiol, and Cyanocobalamin Injection
Estrone Sterile Suspension Veterinary Injection
Etanercept Injection.
Etorphine Hydrochloride Veterinary

Exemestane Aqueous Suspension Injection
Famotidine Injection
Fenoldopam Mesylate Injection
Fentanyl Citrate Injection
Filgrastim Injection
Flosulide Injection
Fluconazole Injection
Flumazenil Injection

© 2004 by CRC Press LLC


Folic Acid and Niacinamide Injection
Follitropin Beta for Injection
Furosemide Injection
Gentamicin and Prednisolone Ophthalmic Drops
Gentamicin Injection
Gentamicin Ophthalmic Drops
Glycine Antagonist Injection
Glycopyrrolate Injection
Granisetron Hydrochloride Injection
Guaiacol-Iodide Solution Veterinary
Haloperidol Injection
Hemin for Injection
Heparin Injection
Hepatitis B Immune Globulin (Human)
Hexamethylmelamine Injection
Hydrochloric Acid
Hydrocortisone Sodium Phosphate Injection
Hydrocortisone Sodium Succinate for Injection

Hydromorphone Hydrochloride Injection
Hydroxycobalamin Injection
Hydroxyprogesterone Caproate Injection
Hydroxypropylmethylcellulose Ophthalmic Solution
Hyoscine Butylbromide Injection
Ibuprofen Lysinate Injection
Ibutilide Fumarate Injection
Idarubicin Hydrochloride Injection
Imiglucerase for Injection
Immune Globulin (Human) for Injection
Infliximab Recombinant for Injection
Insulin Aspart Injection
Insulin Glargine Injection
Insulin Human 70/30
Insulin Human Isophane Suspension (NPH)
Insulin Lispro Injection
Insulin Regular
Interferon Injection
Interleukin for Injection (IL-2)
Iodine Intravenous Additive
Iron Copper Solution Veterinary
Iron Dextran Injection
Iron Sucrose Injection
Isometheptene Hydrochloride Veterinary Injection
Itraconazole Injection
Ketoprofen Lysine Injection
Ketorolac Tromethamine Injection
Ketorolac Tromethamine Ophthalmic Solution
Labetalol Hydrochloride Injection
Lactobionic Acid Injection

Lamotrigine Injection
Lazaroid Injection
Lepirudin for Injection
Leucovorin Calcium Injection
Leuprolide Acetate Injection
Levorphanol Tartarate Injection
Levothyroxine Sodium for Injection

© 2004 by CRC Press LLC


Lidocaine Hydrochloride and Epinephrine Injection
Lidocaine Hydrochloride Injection
Lincomycin Hydrochloride Injection
Liothyronine Sodium Injection (T3)
Lipid Emulsion 20% for Parenteral Nutrition
Liver, Iron, and Cyanocobalamin with Procaine Injection
Liver, Iron, and Vitamin B12 Injection Veterinary
Lorazepam Injection
Magnesium Sulfate 50% Injection
Manganese Sulfate Injection
Mechlorethamine Hydrochloride for Injection Trituration
Medroxyprogesterone Acetate Sterile Aqueous Suspension
Medroxyprogesterone and Estradiol Sterile Suspension
Melphalan Hydrochloride for Injection
Menadione Injection
Menadione Sodium Bisulfite Injection Veterinary
Menotropins for Injection
Meperidine Hydrochloride Injection
Meperidine Hydrochloride and Promethazine Hydrochloride Injection

Mepivacaine Hydrochloride Injection
Meropenem for Injection
Mesoridazine Besylate Injection
Metaraminol Bitartrate Injection
Methandriol Dipropionate Injection
Methocarbamol Injection
Methohexital Sodium for Injection
Methylprednisolone Acetate Suspension Injection
Metoclopramide Injection
Metolazone Injection
Metronidazole Infusion
Metronidazole Injection
Metronidazole and Dextrose Infusion
Midazolam Hydrochloride Injection
Milrinone Lactate Injection
Mineral Complex Injection
Mitoxantrone for Injection .
Morphine Sulfate Infusion .
Morphine Sulfate Injection
Moxidectin Injection
Multiple Electrolytes and Dextrose Injection (Elliott’s B Solution)
Muromonab-CD3 Injection
Nalbuphine Hydrochloride
Naloxone Hydrochloride Injection
Nandrolone Decanoate Injection
Nandrolone Phenylpropionate Injection
Naphazoline Ophthalmic Drops
Natamycin Ophthalmic Suspension
Natural Estrogenic Substances Suspension
Nedocromil Sodium Ophthalmic Solution

Neomycin and Prednisolone Acetate Ophthalmic Suspension
Neomycin Sulfate–Polymyxin B Sulfate for Irrigation
Neostigmine Methylsulfate Injection
Nesiritide for Injection
Netilmicin Injection
Niacinamide Injection

© 2004 by CRC Press LLC


Nicardipine Hydrochloride for Infusion
Nicardipine Hydrochloride Injection
Nikethamide Injection
Nimesulide Injection
Nimodipine Injection
Nystatin for Injection
Octreotide Acetate Injection
Ofloxacin Otic Solution
Ondansetron Hydrochloride Injection
Oprelvekin for Injection
Orphenadrine Citrate Injection
Oxacarbazepine-10 Injection
Oxazepine Injection
Oxendolone Injection
Oxymorphone Hydrochloride Injection
Oxytetracycline Injection
Oxytocin Injection
Oxytocin Injection, USP, 20 U/mL
Paclitaxel Injection
Palivizumab for Injection

Pancuronium Bromide Injection
Parenteral Nutrition Fat Emulsion
Paricalcitol Injection
Pegademase Bovine Injection
Pegaspargase Injection
Peginterferon Alfa-2b for Injection
Penicillin G Benzathine and Penicillin G Procaine Injection
Penicillin G Benzathine Injectable Suspension
Pentobarbital Sodium Solution Injection
Pentostatin for Injection
Pentylenetetrazole Injection
Pheniramine Maleate Injection
Phenol Saline Diluent
Phenylbutazone and Dipyrone Injection
Phenylbutazone Injection Veterinary
Phenylephrine and Zinc Sulfate Ophthalmic Drops
Phenylpropanolamine Hydrochloride Injection
Phenytoin Sodium Injection
Phytonadione (Vitamin K1) Injection
Piperacillin Sodium and Tazobactam Sodium Injection
Plicamycin for Injection
Polyvinyl Alcohol Ophthalmic Solution
Potassium Estrone Sulfate Injection Veterinary
Potassium Estrone Sulfate Suspension Injection
Potassium Phosphate Injection
Prednisolone and Neomycin Ophthalmic Suspension
Prednisolone Injection
Prednisolone Ophthalmic Drops
Procaine Hydrochloride Injection
Prochlorperazine Injection

Progesterone and Tocopheryl Acetate Injection
Progesterone Injection Repository Veterinary
Promazine Hydrochloride Injection
Promethazine Hydrochloride Injection
Propofol Emulsion Injection

© 2004 by CRC Press LLC


Pyridoxine and Thiamine Injection
Pyridoxine Hydrochloride Injection
Pyrilamine Maleate and Ephedrine Injection Veterinary
Quinidine Sulfate Injection
Quinolone Lyophilized Injections
Quinolone–Calcium Lactate Complex for Injection
Ranitidine Injection
Reteplase Recombinant for Injection
Retinol (Vitamin A) Injection
Rho (D) Immune Globulin (Human) Injection
Ringer Lactate Solution Injection
Rituximab Injection
Rubella Virus Vaccine Live
Salbutamol Aerosol for Inhalation
Sisomicin Injection
Sodium Bicarbonate and Disodium Edetate Injection
Sodium Bicarbonate Injection
Sodium Chloride Bacteriostatic Injection
Sodium Chloride Injection
Sodium Ferric Gluconate Complex in Sucrose Injection
Sodium Hyaluronate Injection

Sodium Lactate Compound (Hartmann’s) Injection
Sodium Thiosulfate Injection
Somatropin (rDNA Origin) Injection
Sterile Water for Injection
Streptomycin Sulfate Injection
Succinylcholine Chloride Injection
Sumatriptan Succinate Injection
Tenecteplase for Injection
Testosterone Injection
Tetrahydrozoline Ophthalmic Drops
Theophylline and Dextrose Injection
Thiamine Hydrochloride Injection
Thiopental Sodium for Injection
Thiotepa for Injection
Thiothixene Hydrochloride Injection
Thyrotropin Alfa for injection
Timolol Ophthalmic Solution
Tinzaparin Sodium Injection
Tirofiban Hydrochloride Injection
Tobramycin Solution for Inhalation
Tobramycin Sulfate Injection
Topotecan Hydrochloride for Injection
Trace Element Concentrate Injection
Tranexamic Acid Injection
Trastuzumab for Injection
Triamcinolone Acetonide Suspension Injection
Triflupromazine Hydrochloride Injection
Tripelennamine Hydrochloride Injection Veterinary
Tubocurarine Chloride Injection
Typhoid Vi Polysaccharide Vaccine

Uridine Triphosphate Injection
Urokinase for Injection
Valproate Sodium Injection
Valrubicin for Intravesical Instillation

© 2004 by CRC Press LLC


Vancomycin for Injection.
Varicella Virus Vaccine Live
Vasopressin (8-Arginine Vasopressin) Injection
Vecuronium Bromide for Injection
Verapamil Hydrochloride Injection
Vinblastine Sulfate for Injection
Vincristine Sulfate Injection
Water for Injection
Water for Injection, Bacteriostatic
Zinc Sulfate Additive Injection
Zoledronic Acid for Injection

© 2004 by CRC Press LLC


Part II
Sterile Pharmaceutical Formulations

© 2004 by CRC Press LLC


Sterile Pharmaceutical Formulations

65

Abciximab Injection
Bill of Materials (Batch Size 1 L)
Scale /mL
2.00 mg
0.01 M
0.15 M
0.001 %
QS mL

Item
1
2
3
4
5

Material
Abciximab
Sodium Phosphate
Sodium Chloride
Polysorbate 80
Water for Injection, QS to

MANUFACTURING DIRECTIONS
1. Abciximab is the Fab fragment of the chimeric
human-murine monoclonal antibody 7E3.
2. Abciximab binds to the glycoprotein (GP)

IIb/IIIa receptor of human platelets and inhibits
platelet aggregation. Abciximab also binds to
the vitronectin (alphavbeta3) receptor found on
platelets and vessel wall endothelial and smooth
muscle cells.

Quantity
2.00
0.01
0.15
0.001
1.00

UOM
g
M
M
%
L

3. The chimeric 7E3 antibody is produced by continuous perfusion in mammalian cell culture.
The 47,615 Da Fab fragment is purified from
cell culture supernatant by a series of steps
involving specific viral inactivation and
removal procedures, digestion with papain, and
column chromatography.
4. It is a clear, colorless, sterile nonpyrogenic
solution for intravenous (IV) use (pH 7.2). No
preservatives are added.

Acetazolamide Injection
Bill of Materials
Scale/Vial
500.00 mg
QS mL
QS mL
a

Item

Material
Acetazolamide Sodium
Sodium Hydroxidea
Hydrochloric Acida

For pH adjustment.

DESCRIPTION
Supplied as a sterile powder requiring reconstitution. The
bulk solution is adjusted to pH 9.2 prior to lyophilization.

© 2004 by CRC Press LLC

Quantity
500.00
QS
QS

UOM
mg

mL
mL


66

Handbook of Pharmaceutical Manufacturing Formulations: Sterile Products

Acetylcholine Chloride Intraocular Solution
Bill of Materials for Lower Chamber
Scale/Vial
20.00 mg
56.00 mg

Item
1
2

Material
Acetylcholine Chloride
Mannitol

Quantity UOM
20.00 mg
56.00 mg

Bill of Materials for Upper Chamber (2-mL Diluent)
Sodium Acetate Trihydrate
Potassium Chloride
Magnesium Chloride Hexahydrate

Calcium Chloride Dihydrate
Sterile Water for Injection

DESCRIPTION
Acetylcholine chloride intraocular solution is a parasympathomimetic preparation for intraocular use packaged in
a vial of two compartments. The reconstituted liquid will
be a sterile isotonic solution (275 to 330 milliosmoles/kg)

containing 20 mg acetylcholine chloride (1:100 solution)
and 2.8% mannitol. The pH range is 5.0 to 8.2. mannitol
is used in the process of lyophilizing acetylcholine chloride, and is not considered an active ingredient.

Acyclovir Sodium Injection
Bill of Materials per Vial (10 mL)
Scale/mL
50.00 mg
4.90 mg
QS mL

Item
1
2
3

Material
Acyclovir
Sodium
Sterile Water for Injection, USP (for reconstitution)

DESCRIPTION

Acyclovir sodium for injection is a sterile lyophilized
powder for intravenous administration only. The pH of the

© 2004 by CRC Press LLC

Quantity
500.00
49.00
10.00

UOM
mg
mg
mL

reconstituted solution is ca. 11. Further dilution in any
appropriate intravenous solution must be performed
before infusion.


Sterile Pharmaceutical Formulations

67

Adenosine Injection
1: 5¢ Monophosphate Injection 200 mg/mL Veterinary
Bill of Materials (Batch Size 1 L)
Scale/mL
200.00 mg
1.50 %

QS mL
QS mL

Item
1
2
3
4

Material
Adenosine 5¢ Monophosphate
Benzyl Alcohol, NF
Water for Injection, USP, QS to
Sodium Hydroxide for pH adjustment

Quantity
200.00
1.50
1.00
QS

UOM
g
%
L
mL

Quantity
3.00
9.00

1.00

UOM
g
g
L

2: Adenosine Injection
Bill of Materials (Batch Size 1 L)
Scale/mL
3.00 mg
9.00 mg
QS mL

Item
1
2
3

Material
Adenosine
Sodium Chloride
Water for Injection, QS to

Adjust pH to 4.7 to 5.0.

Adrenal Cortex Injection
Bill of Materials (Batch Size 1 L)
Scale/mL
200.00 mg

1:20,000
QS
QS
QS

—
mL
mL
mL

Item
1
2
3
4
5

Material
Adrenal Cortex equivalent to 200 mg Hydrocortisone Reference
Standard, USP
Thimerosal as preservative
Water for Injection, USP, QS to
Sodium Acetate for buffering
Acetic Acid for buffering

Quantity UOM
200.00 mg
1:20,000
1.00
QS

QS

—
L
mL
mL

Adrenaline Tartarate Injection
Bill of Materials (Batch Size 1 L)
Scale/mL
1.80 mg
1.00 mg
8.00 mg
QS L
a

Item
1
2
3
4

Material
Adrenaline Bitartarate (1:1000)a
Sodium Metabisulfite
Sodium Chloride NF
Water for Injection, USP, QS to

Quantity
1.80

1.00
8.00
1.00

UOM
g
g
g
L

Contains not less than 0.09% and not more than 0.115% w/v of adrenaline.

MANUFACTURING DIRECTIONS
1. Boil Item 4 and allow to cool to room temperature; check for suitability by pH and electrical
conductivity.
2. Add and mix Items 1, 2, and 3 and stir to dissolve all ingredients.

© 2004 by CRC Press LLC

3.
4.
5.
6.
7.

Check and record pH 2.9 to 3.6. Sample.
Filter through 0.22-mm filter.
Fill 1.1 mL into amber ampoules.
Heat-sterilize at 121∞C for 30 min. Sample.
Check for clarity. Sample.